Composite mesh design for delivery of autologous mesenchymal stem cells influences mesh integration, exposure and biocompatibility in an ovine model of pelvic organ prolapse

Emmerson, Stuart; Mukherjee, Shayanti; Melendez‐Munoz, Joan; Cousins, Fiona L.; Edwards, Sarah C.; Karjalainen, P; Ng, Michael; Tan, Ker Sin; Darzi, Saeedeh; Bhakoo, Kishore; Rosamilia, Anna; Werkmeister, Jerome A.; Gargett, Caroline E.

doi:10.1016/j.biomaterials.2019.119495

Cited by 42 publications

(33 citation statements)

References 46 publications

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“…Bodek et al, 2015), sheep (Letouzey et al, 2015;Emmerson et al, 2019), cow (Cabezas et al, 2014), goat (Tamadon et al, 2017), horse (Cabezas et al, 2018) and non-human primates (Padykula et al, 1989;Wolff et al, 2015) (Table 1). Labelretention, plastic adherence or specific surface markers have been used to isolate endometrial MSC and demonstrate properties similar to human eMSC and bmMSC.…”

Section: Endometrial Msc In Other Speciesmentioning

confidence: 99%

Endometrial and Menstrual Blood Mesenchymal Stem/Stromal Cells: Biological Properties and Clinical Application

Bozorgmehr

Gurung

Darzi

et al. 2020

Front. Cell Dev. Biol.

147

116

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Section: Endometrial Msc In Other Speciesmentioning

confidence: 99%

Endometrial and Menstrual Blood Mesenchymal Stem/Stromal Cells: Biological Properties and Clinical Application

Bozorgmehr

Gurung

Darzi

et al. 2020

Front. Cell Dev. Biol.

147

116

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“…The prolapsed vaginal micro-environment can further be affected when, during treatment for POP, vaginal reconstruction is performed using polypropylene meshes that are stiffer than the native tissues. Indeed, stiffer meshes used as treatment for POP have been shown to produce more adverse events [11][12][13], and it has recently been suggested in an animal model with POP, that construct stiffness is the main driver of treatment failure [14].…”

Section: Introductionmentioning

confidence: 99%

Extracellular Matrix Stiffness and Composition Regulate the Myofibroblast Differentiation of Vaginal Fibroblasts

Ruiz‐Zapata

Heinz

Kerkhof³

et al. 2020

IJMS

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Fibroblast to myofibroblast differentiation is a key feature of wound-healing in soft tissues, including the vagina. Vaginal fibroblasts maintain the integrity of the vaginal wall tissues, essential to keep pelvic organs in place and avoid pelvic organ prolapse (POP). The micro-environment of vaginal tissues in POP patients is stiffer and has different extracellular matrix (ECM) composition than healthy vaginal tissues. In this study, we employed a series of matrices with known stiffnesses, as well as vaginal ECMs, in combination with vaginal fibroblasts from POP and healthy tissues to investigate how matrix stiffness and composition regulate myofibroblast differentiation in vaginal fibroblasts. Stiffness was positively correlated to production of α-smooth muscle actin (α-SMA). Vaginal ECMs induced myofibroblast differentiation as both α-SMA and collagen gene expressions were increased. This differentiation was more pronounced in cells seeded on POP-ECMs that were stiffer than those derived from healthy tissues and had higher collagen and elastin protein content. We showed that stiffness and ECM content regulate vaginal myofibroblast differentiation. We provide preliminary evidence that vaginal fibroblasts might recognize POP-ECMs as scar tissues that need to be remodeled. This is fundamentally important for tissue repair, and provides a rational basis for POP disease modelling and therapeutic innovations in vaginal reconstruction.

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“…Preclinical animal studies showed that eMSC are a promising cell source for treatment of gynecological disorders, including pelvic organ prolapse ( Darzi et al, 2016 ; Gargett et al, 2019 ). For example, eMSC seeded or bio-printed onto meshes with biomechanical properties matching the human vagina (e.g., non-degradable polyamide/gelatin composite meshes) ( Ulrich et al, 2014 ; Emmerson et al, 2019 ), or on degradable nanofibers ( Mukherjee et al, 2019b ; Paul et al, 2019 ), promote angiogenesis, collagen deposition, and cellular infiltration into biomaterials when transplanted into rodent or ovine models. They also elicit an early inflammatory response, characterized first by influx of M1 macrophages, which then switch to the M2 wound healing phenotype ( Ulrich et al, 2014 ; Darzi et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Impact of Sustained Transforming Growth Factor-β Receptor Inhibition on Chromatin Accessibility and Gene Expression in Cultured Human Endometrial MSC

Lucciola

Vrljicak

Gurung

et al. 2020

Front. Cell Dev. Biol.

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Endometrial mesenchymal stem cells (eMSC) drive the extraordinary regenerative capacity of the human endometrium. Clinical application of eMSC for therapeutic purposes is hampered by spontaneous differentiation and cellular senescence upon large-scale expansion in vitro . A83-01, a selective transforming growth factor-β receptor (TGFβ-R) inhibitor, promotes expansion of eMSC in culture by blocking differentiation and senescence, but the underlying mechanisms are incompletely understood. In this study, we combined RNA-seq and ATAC-seq to study the impact of sustained TGFβ-R inhibition on gene expression and chromatin architecture of eMSC. Treatment of primary eMSC with A83-01 for 5 weeks resulted in differential expression of 1,463 genes. Gene ontology analysis showed enrichment of genes implicated in cell growth whereas extracellular matrix genes and genes involved in cell fate commitment were downregulated. ATAC-seq analysis demonstrated that sustained TGFβ-R inhibition results in opening and closure of 3,555 and 2,412 chromatin loci, respectively. Motif analysis revealed marked enrichment of retinoic acid receptor (RAR) binding sites, which was paralleled by the induction of RARB , encoding retinoic acid receptor beta (RARβ). Selective RARβ inhibition attenuated proliferation and clonogenicity of A83-01 treated eMSC. Taken together, our study provides new insights into the gene networks and genome-wide chromatin changes that underpin maintenance of an undifferentiated phenotype of eMSC in prolonged culture.

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Composite mesh design for delivery of autologous mesenchymal stem cells influences mesh integration, exposure and biocompatibility in an ovine model of pelvic organ prolapse

Cited by 42 publications

References 46 publications

Endometrial and Menstrual Blood Mesenchymal Stem/Stromal Cells: Biological Properties and Clinical Application

Endometrial and Menstrual Blood Mesenchymal Stem/Stromal Cells: Biological Properties and Clinical Application

Extracellular Matrix Stiffness and Composition Regulate the Myofibroblast Differentiation of Vaginal Fibroblasts

Impact of Sustained Transforming Growth Factor-β Receptor Inhibition on Chromatin Accessibility and Gene Expression in Cultured Human Endometrial MSC

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